Antibacterial compounds

ABSTRACT

A thiol acid and esters thereof of formula (II): ##STR1## wherein R is hydrogen, a salt forming ion or a pharmaceutically acceptable ester-forming radical, have antibacterial and antimycoplasmal activity and are therefore useful in the treatment of human and veterinary bacterial and mycoplasmal infections.

This invention relates to antibacterial compounds and in particular to athiol acid and esters thereof which have antibacterial activity againstcertain Gram-positive and Gram-negative organisms, and also possessantimycoplasmal activity. The compounds are therefore of value in thetreatment of human and veterinary bacterial and mycoplasmal infections.

Our British cognate patent application No. 24712/76, 40472/76 and8647/77 discloses an acid of formula (I): ##STR2## which will bereferred to herein as `monic acid A.` Although this compound does notappear to have antibacterial or antimycoplasmal activity, esters thereofdo possess antibacterial and antimycoplasmal activity, as disclosed inour British cognate application No. 23536/77, 23548/77 and 23549/77.

It has now been found that certain thiol esters of monic acid A alsopossess antibacterial activity and antimycoplasmal activity.

Accordingly the present invention provides a compound of formula (II):##STR3## wherein R is hydrogen, a salt-forming ion or a pharmaceuticallyacceptable ester-forming radical.

The compound (II) of this invention incorporates a trisubstituted doublebond and may therefore exist in both the E (natural) and Z (or iso)geometrical forms. It is to be understood that both geometrical isomersof the compound of formula (II) are included within the scope of thisinvention, as well as mixtures of the two isomers.

When the group R is a salt-forming radical, the salts may bepharmaceutically acceptable, but need not be, as the utility of compound(II) when R is hydrogen or a salt-forming radical is as an intermediate.Suitable salts of the compound include metal salt, e.g. aluminium,alkali metal salts, such as sodium or potassium, alkaline earth metalsalts, such as calcium or magnesium, and ammonium or substitutedammonium salts for example those with lower alkylamines such astriethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine,bis(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine, or with procaine,dibenzylamine, N,N-dibenzyl-ethylenediamine, 1-ephenamine,N-ethylpiperidine, N-benzyl-α-phenethylamine, dehydroabietylamine,N,N'-bis-dehydroabietylethylenediamine, or bases of the pyridine typesuch as pyridine, collidine, or quinoline.

Suitable ester-forming radicals for the group R include

(a) C₁₋₂₀ alkyl, C₂₋₈ alkenyl of C₂₋₈ alkynyl each of which may beoptionally substituted by C₃₋₇ cycloalkyl, halogen, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl, mono- or di-(C₁₋₆)alkylcarbamoyl, aryl,heterocyclyl, hydroxy, C₁₋₆ alkanoyloxy, amino, mono- anddi-(C₁₋₆)alkylamino, C₁₋₆ alkanoylamino;

(b) C₃₋₇ cycloalkyl optionally substituted with C₁₋₆ alkyl;

(c) aryl;

(d) heterocyclyl.

The term "aryl" included phenyl, and naphthyl optionally substitutedwith up to five halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo(C₁₋₆)alkyl,hydroxy, amino, carboxy, C₁₋₆ alkoxycarbonyl, or C₁₋₆ alkoxycarbonyl(C₁₋₆)alkyl groups.

The term "heterocyclyl" includes single or fused rings comprising up tofour hetero atoms in the ring selected from oxygen, nitrogen and sulphurand optionally substituted with up to three halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, halo(C₁₋₆)alkyl, hydroxy, amino, carboxy, C₁₋₆ alkoxycarbonyl,C₁₋₆ alkoxycarbonyl(C₁₋₆)alkyl, aryl or oxo groups.

Suitable heterocyclyl groups include pyridyl thienyl and furyl.

One suitable substituted alkyl group for the group R has the formula(III):

    --(CH.sub.2).sub.n CO.sub.2 R.sup.1                        (III)

wherein n is an integer from 1 to 20 and R¹ is hydrogen, apharmaceutically acceptable salt-forming ion or C₁₋₆ alkyl.

Thus the group R in compound (II) may be for example C₁₋₆ alkyl, inparticular, methyl, ethyl n- or iso-propyl, n-, sec-, iso- ortert-butyl; haol-(C₁₋₆)-alkyl such as trifluoromethyl, 2-chloroethyl,2,2,2-trichloroethyl; aminoalkyl groups such as aminomethyl,2-aminoethyl; hydroxymethyl, 2-hydroxyethyl; phenyl; substituted phenyl;a benzyl group; or a group of formula (III) wherein n is an integer from1 to 8.

One sub-group of compounds of this invention comprises those wherein Ris hydrogen, an alkali metal, C₁₋₂₀ alkyl or C₂₋₈ alkenyl optionallysubstituted with phenyl or C₁₋₆ alkanoylamino; phenyl, or a group offormula (III) above.

Preferred values for R include C₁₋₆ alkyl and C₂₋₆ alkenyl.

Other specific examples of the group R include: C₇₋₂₀ alkyl groups suchas heptyl, octyl, nonyl, decyl and dodecyl; cyclopropyl,cyclopropylmethyl, cyclopentyl, cyclohexyl, carboxymethyl,methoxycarbonylmethyl, 2-carboxyethyl, 2-methoxycarbonylethyl,3-methoxycarbonylpropyl, 4-methoxycarbonyl-n-butyl,5-methoxycarbonyl-n-pentyl, 6-methoxycarbonyl-hexyl,7-methoxycarbonyl-n-heptyl, 10-methoxycarbonyldecyl, carbamoylmethyl,furylmethyl, benzyl, 2,4,6-trichlorophenyl, pentachlorophenyl, o-, m- orp-methylphenyl, o-, m- or p-methoxycarbonylphenyl, 2- or 3- or4-pyridyl, prop-2-enyl, prop-2-ynyl, 2-dialkylaminoethyl, or3-methoxycarbonylprop-2-enyl.

Specific compounds of the present invention include the following estersof monic acid A:

phenylthiol (R=--C₆ H₅);

ethanethiol (R=--C₂ H₅);

benzylthiol (R=--CH₂ C₆ H₅);

n-butanethiol (R=n--C₄ H₉);

methanethiol (R=CH₃);

1-methoxycarbonylmethanethiol (R=--CH₂ CO₂ CH₃);

2-acetamidoethanethiol (R=--CH₂ CH₂ NHCOCH₃);

prop-2-enethiol (R=--CH₂ --CH=CH₂).

The compounds of the present invention may be prepared by reacting monicacid A of formula (I) above, or a reactive derivative thereof with athiol of formula RSH or a reactive derivative thereof.

The choice of reactive derivative for monic acid A will depend onwhether a reactive derivative of the thiol RSH is employed; and willalso be influenced by the nature of the group R.

The reactive derivative of monic acid A may be a symmetrical or mixedanhydride. Suitable mixed anhydrides are alkoxyformic anhydrides, oranhydrides with, for example, alkanoic acids such as trimethyl aceticacid, thioacetic acid, diphenylacetic acid; or with benzoic acid,phosphorus acids (such as phosphoric or phosphorous acids), sulphuricacid or aliphatic or aromatic sulphonic acids (such asp-toluenesulphonic acid). Anhydrides with alkanoic acids such astrimethylacetic acid are suitable when R is an aryl or heterocyclicgroup (type (c) or (d) above) such as phenyl and the anhydride of monicacid A may be reacted directly with the thiol RSH. Alkanoic acid mixedanhydrides are however less suitable when the group R is of the type (a)or (b) above, especially alkyl or substituted alkyl. In this case othermixed anhydrides, such as with phosphorus acids, may be employed. Apreferred manner of preparing compounds (II) when R is an alkyl orsubstituted alkyl group is reacting the mixed anhydride formed frommonic acid A and diethyl phosphorochloridate with a thiolate salt, M⁺ S⁻R, where M⁺ is a metal ion such as thallium (I) or an alkali metal suchas sodium or potassium.

Other suitable reactive derivatives of monic acid A include an acidhalide, preferably the acid chloride or bromide which may be reactedwith a salt of the thiol RSH. The acid halide may be prepared byreacting the monic acid or a salt thereof with a halogenating agent suchas phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Activated esters of monic acid A may also be employed as reactivederivatives. Examples include esters of N-hydroxysuccinimide,1-hydroxy-1H-benzo-triazole,3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, pentachlorophenol andthe enol ester from 4-dimethylamino-3-butyn-2-one.

Other reactive derivatives of monic acid A include the reactiveintermediate formed by reaction in situ with a condensing agent such asa carbodiimide optionally together with 4-dimethylaminopyridine, forexample N,N-diethyl-, dipropyl- or diisopropylcarbodiimide,N,N'-di-cyclohexylcarbodiimide, orN-ethyl-N'-γ-dimethylaminopropylcarbodiimide; a suitable carbonylcompound, for example N,N'-carbonyldiimidazole orN,N'-cabonylditriazole; an isoxazolinium salt, for exampleN-ethyl-5-phenylisoxazolinium-3-sulphonate orN-t-butyl-5-methylisoxazolinium perchlorate; or anN-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinoline, such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Other condensing agentsinclude Lewis acids (for example BBr₃ --C₆ H₆); or a phosphoric acidcondensing agent such as diethylphosphorylcyanide. The reaction ispreferably carried out in an organic reaction medium, for exampledichloromethane, dimethylformamide, acetonitrile, alcohol, benzene,dioxan, or tetrahydrofuran. A preferred condensing agent isdicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine.

The compound of formula (II) in which R represents hydrogen may also beprepared by the above process. Preferably when R is hydrogen, eithermonic acid A is reacted with hydrogen sulphide or a mixed anhydrode ofthe acid is reacted with a thiolate salt, such as sodium thiolate, NaSH.

The compounds of the present invention also may be prepared from theintermediate ketone of formula (IV) by any method known to convert aketone into an α,β-unsaturated thio-acid or ester. One such processcomprises reacting a compound of formula (IV) in which the hydroxylhydroxyl groups may be protected with a compound of formula (V) or (VI):##STR4## in which formulae (V) and (VI) the symbols R_(a), R_(b) andR_(c) are the same or different and each is lower alkyl, aryl oraralkyl, and R is as defined with respect to formula (II) above; andsubsequently removing any hydroxyl protecting groups.

The preferred embodiment of this process comprises reacting compound(IV) with compound (V). Preferably in this case R_(a) and R_(b) aremethyl or ethyl. In the case when compound (IV) is reacted with compound(VI), then R_(a), R_(b) and R_(c) are preferably all phenyl.

The reaction is usually carried out in an inert solvent such asdimethylformamide, hexane, benzene, tetrahydrofuran for example, at atemperature of from about 10° C. to about 100° C. preferably under aninert gas such as nitrogen. Under these conditions the reaction proceedssmoothly over a period of from a few minutes to a few hours and theproduct may be isolated by any of the usual techniques e.g. solventevaporation or anti-solvent precipitation followed by filtration. Inmany cases the reaction may be carried out in a solvent in which theproduct is insoluble and in such cases the precipitated solid may becollected by filtration. Purification of the product may be by any ofthe usual chromatographic or recrystallisation techniques.

Compounds of formula (II) wherein R is an ester-forming radical may alsobe prepared by esterification of compound (II) wherein R is hydrogen ora salt or other reactive derivative of the acid. Esterification may beperformed by any conventional method, for example by reaction of thefree acid:

(a) with the appropriate thiol or alcohol in the presence of a catalystsuch as a strong acid, dry hydrogen chloride or p-toluenesulphonic acid;or

(b) with the appropriate halide or sulphate of the alcohol in thepresence of dimethylsulphoxide and calcium carbonate or with the halidein the presence of hexamethyl phosphoramide; or

(c) by phase transfer catalysis methods with the halide and/or sulphateof the alcohol in aqueous and/or organic solution in the presence of aquaternary ammonium salt such as tetrabutyl ammonium bisulphate orhalide, or benzyltrimethylammonium halide; or

(d) with a diazoalkane.

The antibiotic compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibiotics, and the invention thereforeincludes within its scope a pharmaceutical composition comprising acompound of formula (II) above together with a pharmaceutical orveterinary carrier or excipient.

The compositions may be formulated for administration by any route, andwould depend on the disease being treated. The compositions may be inthe form of tablets, capsules, powders, granules, lozenges, or liquidpreparations, such as oral or sterile parenteral solutions orsuspensions.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrollidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired convention flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa,butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lypophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionsare prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and sterilizationcannot be accomplished by filtration. The compound can be sterilized byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, or the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg., of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg, per day, for instance 1500 mg, per day, depending on theroute and frequency of administration.

The following Examples illustrate this invention.

EXAMPLE 1 Thiophenyl Monate A

Monic acid (0.344 g; 1 mM) was dissolved in dry tetrahydrofuran (20 ml)and the solution cooled to -10° C. Triethylamine (0.101 g; 140 μl; 1 mM)and isobutylchloroformate (0.137 g; 130 μl; 1 mM) were added and thesolution stirred at -10° C. for 15 minutes. Thiophenol (0.110 g; 103 μl;1 mM) was then added and the solution stirred at 0° C. for 30 minutesand room temperature of 2 hours. The solvent was then removed at reducedpressure and the residue partitioned between ethyl acetate and sodiumbicarbonate solution. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulphate. Removal of the solvent atreduced pressure afforded a colourless oil, which was purified by columnchromatography over silica gel (12 g; Type 60). Elution with 5%methanol/chloroform yielded the pure (hplc and tlc) thiophenyl monate asan oil, which on trituration with dry diethyl ether gave a white solid(0.200 g; 46%). M.pt. 118°-119° C. (Found: C, 63.12; H, 7.39; S, 7.36.C₂₃ H₃₂ O₆ S requires: C, 63.28; H, 7.39; S, 7.34%). [α]_(D) ²⁰ =-41.7°(c 1.0, CHCl₃), λ_(max) (EtOH) 240 nm (ε_(m) 19,400), 264 (ε_(m)10,400), ν_(max) (CHBr₃) 3400, 1685 and 1620 cm⁻¹ δ_(H) (CDCl₃) 7.33(5H, s, aromatic protons), 6.10 (1H, s, CH═C), ##STR5## 1.20 (3H, d,J=6.5 Hz, CH₃ --14), 0.91 (3H, d, J=7.0 Hz, CH₃ --17), δ_(C) (CD₃ OD)188.8 (s), 158.0 (s), 135.7 (d), 130.1 (d), 129.8 (s), 124.3 (d), 116.8(d), 76.2 (d), 71.6 (d), 69.9 (d) 66.4 (t), 61.3 (d), 56.9 (d), 43.7,41.6 (d), 32.9 (t), 20.4 (q), 12.3 (q).

EXAMPLE 2 Thioethyl Monate A

To a solution of monic acid (0.344 g; 1 mM) and triethylamine (0.101 g;140 μl; 1 mM) in dry tetrahydrofuran (10 ml) was added a solution ofdiethyl phosphorochloridate (0.173 g; 1 mM) in dry tetrahydrofuran (5ml), at room temperature under an argon atmosphere. The mixture wasstirred at room temperature for 3 hours, and the precipitatedtriethylamine hydrochloride was removed by filtration. The solid waswashed with tetrahydrofuran and to the combined filtrate and washingswas added thallium (I) ethanethiolate (0.265 g; 1 mM). The resultingsuspension was stirred at room temperature for three days and thenfiltered through a celite plug. The solvent was removed at reducedpressure and the residue partitioned between ethyl acetate and sodiumbicarbonate solution. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulphate. Removal of the solvent atreduced pressure gave the crude thiol ester as a colourless oil (0.380g). This oil was purified by column chromatography over silica gel (Type60; 10 g). Elution with 5% methanol/chloroform afforded the pure (byhplc and tlc) thoiethyl monate as a colourless oil. Trituration with drydiethyl ether gave a white solid (0.205 g; 53%). M.pt. 80°-81° C.(Found: C, 59.03; H, 8.24; S, 8.38. C₁₉ H₃₂ SO₆ requires: C, 58.74; H,8.30; S, 8.25%). [α]_(D) ²⁰ -8.3°, (c 1.0, CHCl₃), λ_(max) (EtOH) 237 nm(ε_(m) 9,682), 268 nm (ε_(m) 8,150), ν_(max) (nujol) 3425, 1680 and 1620cm⁻¹, δ_(H) (CDCl₃) 6.0 (1H, s, CH═C); ##STR6## 1.25 (6H, t, CH₃ --14and SCH₂ CH₃); 0.92 (3H, d, J=7.0 Hz, CH₃ --17), δ_(C) (CDCl₃) 189.6,153.6, 124.7, 74.9, 71.3, 70.3, 68.9, 65.4, 61.3, 55.6, 42.8, 42.6,39.5, 31.6, 23.2, 20.8, 20.0, 14.8 and 12.7, m/e 227 (5%), 111 (50%), 62(100%), No M⁺.

EXAMPLE 3 Thiobenzyl Monate A

To a solution of monic acid (1.032 g; 3 mM) and triethylamine (0.303 g;420 μl; 3 mM) in dry tetrahydrofuran (30 ml) was added a solution ofdiethyl phosphorochloridate (0.518 g; 3 mM) in dry tetrahydrofuran (10ml), at room temperature under an argon atmosphere. The solution wasstirred at room temperature for three hours and the precipitatedtriethylamine hydrochloride was removed by filtration. To the filtratewas added thallium (I) benzylthiolate (0.981 g; 3 mM). The resultingsuspension was stirred at room temperature for 16 hours and thenfiltered through a celite plug. The solvent was removed at reducedpressure and the residue partitioned between ethyl acetate and sodiumbicarbonate solution. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulphate. Removal of the solvent atreduced pressure gave the crude thiol ester as a colourless oil (1.0 g).This oil was purified by column chromatography over silica gel (Type 60;25 g). Elution with 5% methanol/chloroform afforded the pure (by hplcand tlc) thiobenzyl monate as a colourless oil (0.730 g; 54%). μ_(max)(EtOH) 235 nm (ε_(m) 10, 950), 270 nm (ε_(m) 8,300), ν_(max) (CHBr₃)3400, 1670 and 1620 cm⁻¹, δ_(H) (CDCl₃) 7.18 (5H, m, aromatic H); 5.98(1H, s, CH═C); 4.07 (2H, s, SCH₂); 2.18 (3H, s, CH₃ --15); 1.17 (3H, d,J=6.0 Hz, CH₃ --14); 0.88 (3H, d, J=6.0 Hz, CH₃ --17), δ_(C) (CDCl₃)188.1, 154.7, 137.7, 129.0, 128.5, 128.2, 126.7, 123.6, 74.6, 70.4,69.9, 68.5, 65.1, 60.6, 55.2, 42.3, 39.4, 32.7, 31.3, 20.2, 19.9, 12.1,m/e 327.1808 (C₁₇ H₂₇ O₆ requires 327.1808; 0.2%), 281 (2%), 263 (25%),246 (6%), 235 (13%), 132 (10%), 131 (20%), 91 (100%), No M⁺. [α]_(D) ²⁰-6.11° (c 1.0, CHCl₃).

EXAMPLE 4 n-Butanethiol Ester of Monic Acid A

To a solution of monic acid (1.032 g; 3 mM) and triethylamine (0.30 g;420 μl; 3 mM) in dry tetrahydrofuran (30 ml) was added a solution ofdiethyl phosphorochloridate (0.518 g; 3 mM) in dry tetrahydrofuran (10ml), at room temperature under an argon atmosphere. The mixture wasstirred at room temperature for three hours, and the precipitatedtriethylamine hydrochloride was removed by filtration. To the filtratewas added thallium (I) n-butanethiolate (0.879 g; 3 mM). The resultingsuspension was stirred at room temperature for 16 hours and thenfiltered through a celite plug. The solvent was removed at reducedpressure and the residue partitioned between ethyl acetate and sodiumbicarbonate solution. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulphate. Removal of the solvent atreduced pressure gave the crude thiol ester as a colourless oil (1.10g). This oil was purified by column chromatography over silica gel (Type60; 15 g). Elution with 5% methanol/chloroform afforded the pure (byhplc and tlc) n-butanethiol ester of monic acid as a colourless oil(0.957 g; 77%). λ_(max) (EtOH) 238 nm (ε_(m) 10,600), 270 nm (ε_(m)8,770), ν_(max) (CHBr₃) 3420, 1670 and 1620 cm⁻¹, δ_(H) (CDCl₃) 6.0 (1H,s, CH═C); ##STR7## 1.19 (3H, d, J=6.5 Hz, CH₃ --14); 0.91 (6H, d+t, CH₃--17 and alkyl CH₃), δ_(C) (CDCl₃) 189.3, 153.5, 124.3, 74.7, 70.5,70.0, 68.6, 65.0, 60.7, 55.3, 42.4, 39.3, 31.4, 28.2, 21.7, 20.3, 19.7,13.3, and 12.2. m/e 327.1806 (C₁₇ H₂₇ O₆ requires 327.1808; 3%), 300(4%), 227 (12%), 111 (30%), 101 (100%). No M⁺. [α]_(D) ²⁰ -7.15° (c 1.0,CHCl₃).

EXAMPLE 5 Methanethiol Ester of Monic Acid A

To a solution of monic acid (2.064 g; 6 mM) and triethylamine (0.840 ml;6 mM) in dry tetrahydrofuran (50 ml) was added diethylphosphorochloridate (1.035 g; 6 mM), at room temperature under an argonatmosphere. The mixture was stirred at room temperature for three hoursand the precipitated triethylamine hydrochloride was removed byfiltration. The solid was washed with tetrahydrofuran and to thecombined filtrate and washings was added thallium (I) methanethiolate(1.506 g; 6 mM). The resulting suspension was stirred at roomtemperature for sixteen hours and then filtered through a celite plug.The solvent was removed at reduced pressure and the residue partitionedbetween ethyl acetate and sodium bicarbonate solution. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulphate. Removal of the solvent at reduced pressure gave the crudethiol ester as a colourless oil. This oil was purified by columnchromatography over silica gel (Type 60; 25 g). Elution with 5%methanol/chloroform afforded the pure methanethiol ester of monic acid Aas a colourless oil, which crystallised with ether (1.10 g; 49%). M.pt.74°-75° C. (ether). (Found: C, 58.0; H, 8.1; S, 8.8 C₁₈ H₃₀ SO₆requires: C, 57.7; H, 8.1; S, 8.6%), [α]_(D) ²⁰ -9.25° (c 1.0 CHCl₃),λ_(max) (EtOH) 237 nm (ε_(m) 12,100), 268 nm (ε_(m) 10,300), ν_(max)(CHBr₃) 3440, 1660 and 1620 cm⁻¹, δ_(H) (CDCl₃) 6.01 (1H, s, CH═C); 2.28(3H, s, --SCH₃); 2.17 (3H, s, CH₃ --15); 1.20 (3H, d, J=6.5 Hz, CH₃--14); 0.91 (3H, d, J=6.0 Hz, CH₃ --17), δ_(c) (CDCl₃) 190.0, 154.0,124.4, 75.0, 70.9, 70.4, 68.9, 65.4, 61.1, 55.7, 42.7, 39.7, 31.6, 20.6,20.1, 12.5, 11.5, m/e 327.1812 (C₁₇ H₂₇ O₆ requires 327.1808; 10%), 227(20%), 169 (10%), 141 (23%), 111 (100%), no M⁺.

EXAMPLE 6 1-Methoxycarbonylmethanethiol Ester of Monic Acid A

To a solution of monic acid (2.06 g; 6 mM) and triethylamine (0.840 ml;6 mM) in dry tetrahydrofuran (50 ml) was added diethylphosphorochloridate (1.035 g; 6 mM), at room temperature under an argonatmosphere. The mixture was stirred at room temperature for three hoursand the precipitated triethylamine hydrochloride was removed byfiltration. The solid was washed with tetrahydrofuran and to thecombined filtrate and washings was added sodium1-methoxycarbonylmethanethiolate (0.768 g; 6 mM). The resultingsuspension was stirred at room temperature for 16 hours and thenfiltered through a celite plug. The solvent was removed at reducedpressure and the residue partitioned between ethyl acetate and sodiumbicarbonate solution. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulphate. Removal of the solvent atreduced pressure gave the crude thiol ester as a colourless oil. Thisoil was purified by column chromatography over silica gel (Type 60; 25g). Elution with 5% methanol/chloroform afforded the pure1-methoxycarbonylmethanethiol ester of monic acid A as a colourless oil,(1.029 g; 40%), [α]_(D) ²⁰ -5.71° (c, 1.0 CHCl₃), λ_(max) (EtOH) 242 nm(ε_(m) 10,400), 265 nm (ε_(m) 9.750), ν_(max) (CHBr₃) 3400, 1735, 1678and 1620 cm⁻¹, δ_(H) (CDClhd 3) 6.02 (1H, s, CH═C); 3.68 (3H, s, CO₂CH₃); 2.18 (3H, s, CH₃ --15); 1.19 (3H, s, J=6.0 Hz, CH₃ --14); 0.92(3H, d, J=6.0 Hz, CH₃ --17), δ_(c) (CDCl₃) 186.9, 170.0, 156.6, 123,4,75.0, 70.8, 70.4, 68.8, 65.6, 65.4, 61.0, 55.7, 52.7, 42.7, 39.8, 31.7,206, 20.4, and 12.5.

EXAMPLE 7 2-Acetamidoethanethiol Ester of Monic Acid A

To a solution of monic acid (1.032 g; 3 mM) and triethylamine (0.420 ml;3 mM) in dry tetrahydrofuran (50 ml) was added diethyl phosphorochloride(0.518 g; 3 mM), at room temperature under an argon atmosphere. Themixture was stirred at room temperature for three hours and precipitatedtriethylamine hydrochloride was removed by filtration. The solid waswashed with tetrahydrofuran and to the combined filtrate and washingswas added the sodium salt of N-acetyl-β-mercaptoethylamine (0.423 g; 3mM). The resulting suspension was stirred at room temperature for threedays and then filtered through a celite plug. The solvent was removed atreduced pressure and the residue partitioned between ethyl acetate andsodium bicarbonate solution. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulphate. Removal of thesolvent at reduced pressure gave the crude thiol ester as a pale yellowoil. This oil was purified by column chromatography over silica gel(Type 60; 50 g). Elution with 5% methanol/chloroform afforded the pure2-acetamidoethanethiol ester of monic acid A as a colourless oil, (0.310g; 23%). [α]_(D) ²⁰ -7.04° (c, 1.0 CHCl₃)ν_(max) (CHBr₃) 3350, 1660 and1625 cm⁻¹, λ_(max) (EtOH) 240 nm (ε_(m) 9,630), 267 nm (ε_(m) 8,390),δ_(H) (CDCl₃) 6.67 (1H, broad resonance, NH); 6.02 (1H, s, CH═C); 2.17(3H, s, CH₃ --15); 1.94 (3H, s, COCH₃); 1.19 (3H, d, J=6.0 Hz, CH₃--14); 0.92 (3H, d, J=6.5 Hz, CH₃ --17), δ_(c) (CDCl₃), 189.3, 171.0,155.7, 124.2, 75.0, 71.1, 70.4, 68.9, 65.5, 61.1, 55.7, 42.8, 39.9,31.7, 28.5, 23.1, 20.8, 20.3, and 12.6. m/e 327.1799 (3% C₁₇ H₂₇ O₆requires 327.1808).

EXAMPLE 8 Prop-2-enethiol Ester of Monic Acid A

To a solution of monic acid (1.032 g; 3 mM) and triethylamine (0.420 ml;3 mM) in dry tetrahydrofuran (50 ml) was added diethylphosphorochloridate (0.518 g; 3 mM), at room temperature under an argonatmosphere. The mixture was stirred at room temperature for 3 hours andthe precipitated triethylamine hydrochloride was removed by filtration.The solid was washed with tetrahydrofuran and to the combined filtrateand washings was added thallium (I) 2-propene-1-thiolate (0.830 g: 3mM). The resulting suspension was stirred at room temperature for 16hours and then filtered through a celite plug. The solvent was removedat reduced pressure and the residue partitioned between ethyl acetateand sodium bicarbonate solution. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulphate. Removal ofthe solvent at reduced pressure gave the crude thiol ester as a yellowoil. This oil was purified by column chromatography over silica gel(Type 60; 50 g). Elution with 5% methanol/chloroform afforded the pureprop-2-enethiol ester of monic acid A as a colourless oil, (0.230 g;19%), λ_(max) (EtOH) 239 nm (ε_(m) 11,220), 269 nm (ε_(m) 9,700),ν_(max) (CHBr₃) 3425, 1675 and 1620 cm⁻¹, δ_(H) (CDCl₃) 6.00 (1H, sCH═C); 5.5-5.95 (1H, m, CH═C); 5.18 (dd, J=16 Hz and 1 Hz); 5.03 (dd,J=9.5 Hz and ca 1 Hz, 2H between 4.9 and 5.3, C═CH₂ protons); 2.17 (3H,s, CH₃ --15); 1.19 (3H, d, J=6.0 Hz, CH₃ --14); 0.91 (3H, d, J=7.0 Hz,CH₃ --17), δ_(c) (CDCl₃) 188.6, 154.4, 133.5, 124.3, 117.6, 75.0, 71.3,70.3, 68.9, 65.5, 61.3, 55.6, 42.9, 39.6, 31.7, 20.8, 20.2, and 12.7,m/e 327.1798 (14%; C₁₇ H₂₇ O₆ requires 327.1807), no M⁺.

EXAMPLE 9 Prop-2-enethiol Ester of Monic Acid A

To a stirred solution of monic acid A (2.064 g; 6 mM) in anhydrousdichloromethane (100 ml) was added 4-dimethylaminopyridine (0.075 g; 0.6mM) and allyl mercaptan (approx. 2 ml; approx. 12 mM). The solution wascooled to 0° C. and dicyclohexylcarbodiimide (1.236 g; 6 mM) was added.The reaction mixture was stirred at 0° C. for 30 minutes and roomtemperature for 16 hours. The solution was then filtered and thefiltrate evaporated at reduced pressure. The residue was then dissolvedin ethyl acetate, washed with sodium bicarbonate solution and saturatedsodium chloride solution and dried over anhydrous magnesium sulphate.Removal of the solvent afforded the crude thiol ester as a yellow oil.This oil was purified by column chromatography over silica gell (Type60; 30 g). Elution with 5% methanol/chloroform afforded the pureprop-2-enethiol ester of monic acid A as a colourless oil (1.16 g; 49%).

BIOLOGICAL DATA

(a) Human Bacteria

Table 1 shows the MIC values (μg/ml) of the compounds of Examples 1 to 8against a number of human pathogens obtained by serial dilution innutrient agar containing 5% `chocolated` horse blood.

                  TABLE 1                                                         ______________________________________                                                  Compound of Example No:                                             Organism    1      2     3   4   5    6    7   8                              ______________________________________                                        Pasteurella                                                                   multocida 1633                                                                            100    1.0   5.0 2.5 0.2   --  2.5 0.5                            Haemophilus                                                                   influenzae Q1                                                                             25     0.2   0.5 0.2 0.05 2.5  0.2 <0.02                          Haemophilus                                                                   influenzae Wy21                                                                           50     0.2   0.5 0.2 0.1  2.5  0.5 0.05                           Neisseria                                                                     catarrhalis 1502                                                                          2.5    0.2   --  --   --  0.05 --  <0.02                          Neisseria                                                                     flavescens 8263                                                                            --    --    0.5 0.2  --   --  0.5  --                            Bacillus subtilis                                                                          --    0.2   0.5 0.2  --  2.5  5.0 0.05                           Staph. aureus                                                                 Oxford      25     0.2   0.5 0.2 0.1  2.5  10  0.05                           Staph. aureus                                                                 Russell      --    0.2   1.0 0.5 0.2  5.0  50  0.2                            Strep. pyrogenes A                                                            64/848      100    0.5   0.2 0.1 2.5  10   5.0 0.5                            Strep. pyrogenes B                                                            2788        100    1.0   2.5 1.0 0.5  5.0  5.0 0.5                            Strep. pyrogenes C                                                            2761        100    1.0   1.0 0.5  --  10   5.0 0.5                            Strep. pneumoniae                                                             CN 33       2.5    2.5   0.2 0.2  --  2.5  2.5 0.2                            ______________________________________                                    

(b) Veterinary Bacteria

Table 2 shows the MIC values (μg/ml) of some of the compounds of theExamples against a number of organisms important in veterinaryinfections.

                  TABLE 2                                                         ______________________________________                                                    Compound of Example No:                                           Organism      2      3      5    6    7    8                                  ______________________________________                                        Bord. brontiseptica                                                           BO9           5      5      5    20   20   5                                  Past. multocida                                                               PA1           0.625  2.5    0.625                                                                              2.5  1.25 1.25                               Past. haemolytica                                                             PA5           5      20     5.0  10   40   5                                  Staph. aureus B4                                                                            0.312  1.25   0.312                                                                              2.5  40   0.312                              Staph. aureus 152                                                                           20     80     0.312                                                                               --  80   40                                 Strep. uberis SPU1                                                                          0.312  0.156  0.625                                                                              1.25 0.625                                                                              0.516                              Strep. dysgalactiae                                                           SPD1          0.625  0.312  5.0  5    2.5  0.625                              Strep. agalactiae                                                             SPA1          0.625  1.25   5.0  5    5    0.625                              ______________________________________                                    

(c) Anti-mycoplasma Activity

Table 3 shows the MIC values (μg/ml) of the compounds of Examples 1 to 8against some important human and veterinary mycoplasma pathogens.

                                      TABLE 3                                     __________________________________________________________________________            Compound of Example No:                                               Organism                                                                              1   2  3  4  5   6   7   8                                            __________________________________________________________________________    (a) Determined in Friis' broth using the microtiter method                    M. suipneu-                                                                   moniae Str. 11                                                                         --  --                                                                               --                                                                               --                                                                              0.156                                                                              -- 0.625 0.156                                      M. suipneu-                                                                   moniae J2206/                                                                         15.6                                                                              <0.5                                                                             <0.5                                                                             <0.5                                                                             0.156                                                                             15.6                                                                              2.5 1.25                                         183 b                                                                         M. dispar H225                                                                         --  --                                                                               --                                                                               --                                                                              <0.02                                                                              -- 0.625                                                                             0.039                                        M. dispar                                                                     NCTC 10125                                                                            <0.5                                                                              <0.5                                                                             <0.5                                                                             <0.5                                                                             <0.02                                                                             <0.5                                                                              0.312                                                                             <0.02                                        M pneumoniae                                                                  427 a   >250                                                                              1.9                                                                              31.25                                                                            3.9                                                                              10  >250                                                                              5.0 10                                           M. pneumoniae                                                                 ATCC 15492   --                                                                               --                                                                               --                                                                              5.0  -- 2.5 5.0                                          M. fermantans                                                                 MWKL4   15.6                                                                              <0.5                                                                             3.9                                                                              <0.5                                                                             <0.02                                                                             15.6                                                                              <0.02                                                                             <0.02                                        M. pulmonis                                                                   JB      15.6                                                                              <0.5                                                                             <0.5                                                                             <0.5                                                                             <0.02                                                                             15.6                                                                              <0.02                                                                             <0.02                                        (b) Determined by serial dilution in Friis agar                               M. bovis                                                                      ATCC 25025                                                                            15.6                                                                              <0.5                                                                             62.5                                                                             3.9                                                                              <0.02                                                                             15.6                                                                              0.039                                                                             0.078                                        M. bovis                                                                      NCTC 10131                                                                             --  --                                                                               --                                                                               --                                                                              <0.02                                                                              -- 0.039                                                                             0.039                                        __________________________________________________________________________

We claim:
 1. A compound of formula: ##STR8## wherein R is apharmaceutically acceptable ester-forming radical.
 2. A compoundaccording to claim 1 wherein R is alkyl of 1 to 20 carbon atoms oralkenyl of 2 to 8 carbon atoms, said alkyl or alkenyl beingunsubstituted or substituted with phenyl or alkanoylamino of 1 to 6carbon atoms; phenyl or

    --(CH.sub.2).sub.n CO.sub.2 R.sup.1

wherein n is an integer from 1 to 20 and R¹ is hydrogen, apharmaceutically acceptable salt-forming ion or alkyl of 1 to 6 carbonatoms.
 3. A compound according to claim 2 wherein R is alkyl of 1 to 6carbon atoms or alkenyl of 1 to 6 carbon atoms.
 4. Methanethiol ester ofmonic acid A.
 5. Ethanethiol ester of monic acid A.
 6. n-Butanethiolester of monic acid A.
 7. Prop-2-enethiol ester of monic acid A.
 8. Apharmaceutical or veterinary composition which comprises anantibacterially or antimycoplasmally effective amount of a compoundaccording to claim 1 in combination with a pharmaceutical or veterinarycarrier or excipient.
 9. The method for the treatment of human andveterinary bacterial and mycoplasmal infections which comprisesadministering to a human or veterinary animal an antibacterially orantimycoplasmally effective amount of a compound according to claim 1.